Upon contact with bone, matrix-derived signals in the RANKL-induced osteoclast (OC) prompt the cell to polarize its cytoskeleton, eventuating in formation of an isolated microenvironment between the polykaryon and skeletal surface. Ultimate degradation of mineralized matrix is mediated by the ruffled border, an OC-unique structure which is the cell's resorptive organelle, contained within this confined space. Thus, the intracellular molecules mediating ruffled border formation and the bone-degrading products they deliver into the resorptive microenvironment are current or potential therapeutic targets. The ruffled border is formed by insertion of lysosome-derived vacuoles into the bone- apposed plasma membrane which we have established occurs under the aegis of synaptotagmin VII (Syt VII). These vesicles contain the vacuolar H+ATPase and cathepsin K which mobilize the mineral and organic phases of bone, respectively. Failure to deliver secretory vesicles to the bone-apposed plasmalemma arrests resorption. Autophagy is a conserved pathway by which proteins and organelles are sequested into autophagosomes and degraded. Like the ruffled border, autophagosomes fuse with lysosomes. Thus, a theoretical commonality exits between the mechanisms of bone resorption and autophagy. In this regard, we find that like SytVII deficiency, absence of the autophagy protein, Atg5, dampens bone degradation by preventing transport of cathepsin K into the resorptive microenvironment. This observation mirrors the failure of vesicle polarization in murine, Atg5-deficient intestinal Paneth cells and those of patients with Crohn's disease. We therefore hypothesize that the autophagy protein, Atg5, mediates RANKL-induced bone resorption by inhibiting secretory vesicle polarization. Thus, our supplemental specific aim is to determine the mechanism by which the autophagy protein, Atg5, mediates RANKL-induced bone resorption. PUBLIC HEALTH RELEVANCE: Inhibition of bone resorption remains our major venue for treating osteoporotic diseases. Information garnered from the supplemental Specific Aim may add to our armamentarium of potential anti-bone resorption therapeutic targets.